Hypercholesterolemia Drugs Flashcards
Which cholesterols cause and inhibit hyperlipidemia?
LDL promotes hyperlipidemia. HDL inhibits hyperlipidemia. Triglycerides promote hyperlipidemia in an unclear way
What are the “good” and “bad” cholesterols?
LDL = bad (Lousy) HDL = good (Happy)
Describe the basic structure of an LDL
Spherical shape.
Phospholipids and cholesterol on the outside along with apoprotein B100. On the inside of the sphere, there are triglycerides and cholesterol esters
What enzyme cleaves fatty acids from chylomicrons in the bloodstream?
Lipoprotein Lipase (LPL)
Where are released fatty acids taken up?
Free fatty acids taken up by adipose tissue (storage) or by muscle (energy production through Beta-oxidation)
Describe the very basic mechanism of atherosclerosis as caused by hyperlipidemia
High LDL infiltrates the vessel wall, leading to development of an atheroma (fatty streak) to cause atherosclerosis
What happens to the LDLs when they enter the intima?
They get oxidized.
What does the oxidation of LDLs cause?
Upregulation of adhesion molecules on the endothelium, leading to monocyte infiltration of the intima
When macrophages swallow LDL, they become….
Foam cells
How do foam cells function?
Secrete growth factors and ECM components. Allows medial smooth muscle to infiltrate into the intima through the IEL. Forms an artherosclerotic plaque!
Describe the protective functions of HDL in prevention of atherosclerosis
Inhibits oxidation of LDLs (PON1 on HDLs has antioxidant activity)
Inhibit adhesion molecule expression on endothelium
Inhibit foam cell formation
Promotes reverse cholesterol transport (from the periphery to the liver to be secreted as bile)
List some causes of Hyperlipidemia
Genetics (Familial Hyperlipidemia -- defect in LDL receptor) High fat/carb diet Age Physical inactivity Alcohol consumption Smoking Diabetes Drugs (HIV antiviral proteases, antipsychotics)
What is the ideal serum level of LDL?
Less than 100mg/dL
What is a very high serum LDL level?
> 190 mg/dL
What is an ideal serum triglyceride level?
Less than 150mg/dL
What is a very high serum triglyceride level?
> 500 mg/dL
Very high serum triglyceride levels increase a patient’s risk of developing…
Pancreatitis
What is the principal goal of treatment for hypercholesterolemia?
Reduce serum LDL levels to hopefully reduce risk of cardiovascular disease
Statins inhibit what enzyme? What does this accomplish?
HMG CoA Reductase
Reduction of serum LDLs
Describe the mechanism by which statins lower LDL levels
Bind HMG CoA reductase and competitively inhibit it. Triggers a signaling pathway that activates SREBP transcription factor to upregulate LDL receptors in cells. Increase LDL uptake from the serum, therefore decreasing serum levels. The LDL’s cholesterol can be excreted in bile
What are some other anti-atherogenic effects of statins?
- Inhibit adhesion molecules on the endothelium.
- Inhibit foam cell production.
- Inhibit smooth muscle proliferation.
- Anti-inflammatory
Does a statin’s ability to decrease CV disease risk depend on LDL levels?
No! Statins decrease risk of CV diseases even in patients with normal LDL levels.
Does increasing the dose of a statin generally cause a greater reduction in LDL?
Not really. Increasing the dose doesn’t have much effect in reducing LDLs, but increased statin dose increases risk of adverse effects
Adverse Effects of Statins
Generally well tolerated.
- Mild GI disturbance
- Increase liver enzymes
- Increase risk of T2DM
- Myalgia/Myopathy
- Rhabdomyolysis
Rhabdomyolysis
What is it? Describe the basic mechanism by which statins can cause it
Inflammation of the muscle followed by disintegration
High levels of statins in the blood allow statins to enter muscles. Cause muscle breakdown, myoglobulin release, kidney damage!
Which statin has a lower risk of developing rhabdomyolysis?
Pravastatin
Statins
Absorption
Well absorbed orally
Statins
Metabolism
Lovastatin, Simvastatin, Atorvastatin are all metabolized by CYP3A4 in the intestine.
Fluvastatin metabolized by CYP2C9
Rosuvastatin metabolized by CYP2C19
Pravastatin is not metabolized by CYP450 enzymes.
Statins
Elimination
Primarily Hepatic, but Pravastatin is both hepatic and renal
Describe potential effects of grapefruit juice with statins
Grapefruit juice inhibits CYP3A4, causing increased serum statin levels, which could cause rhabdomyolysis
List some inducers of CYP3A4 and their potential effects when taken with statin.
Phenytoin, Barbiturates, rifampin are inducers of CYP3A4.
Could decrease clinical efficacy of lovastatin, atorvastatin, and simvastatin
Statins are transported into hepatocytes via what transporter?
OATP2
Gemfibrozil has what effects when taken with statins?
May increase serum concentrations of statins, leading to potential toxicity.
- Competes with statins for OATP2
- Prevent glucoronidation of statins in their metabolism
Statins
Contraindications
Pregnant women and nursing mothers (this may change)
Patients with liver disease (except Pravastatin)
List the Bile Acid Binding Resins
Cholestyramine
Colestipol
Colesevelam
MOA Bild Acid binding Resins
The resins are cationic polymers that can bind negative bile acids. Form an insoluble complex that is excreted into feces. Less recycling of bile acids.
Liver produces more bile acids in response through activation of cholesterol-7-alpha-hydroxylase. Increased LDLR expression on surface, increased uptake of LDL, lower serum LDL
Bile acid binding resins may decrease LDL levels in serum, but what else do they affect?
May increase serum triglycerides
Could cause pancreatitis if triglycerides >500mg/dL
Bile Acid Resins
Therapeutic Uses
Reduce LDL in bloodstream and risk of CV events.
Second line agents that may be used in combination with statins
Bile Acid Resins
Adverse Effects
NOT absorbed or metabolized, so few adverse effects. Minor GI disturbances.
May impair absorption of many drugs (especially anions), so take doses at separate times.
Bile Acid Resins
Contraindications
Increased triglyceride levels (could cause pancreatitis)
Ezetimibe
MOA
Impairs cholesterol absorption from intestine. Inhibits NPC1L1 to lower flux of cholesterol going to the liver, which will increase levels of LDLR expression and increase LDL clearance.
Ezetimibe
Therapeutic Uses
May be used in combination with a statin.
Active in patients with familial hypercholesterolemia.
PCSK9 Inhibitors
Describe their function.
Prevent internalization and degradation of LDLR, thus increasing LDL uptake into liver and lowering serum levels.
List the PCSK9 inhibitors
Alirocumab
Evolocumab
(Both antibodies administered IV)
PCSK9 Inhibitors
Therapeutic Uses
Lower serum LDL levels.
Used in patients with heterozygous FH and patients that have not achieved goals with max tolerated statins
What are the two drugs used in treatment of homozygous familial hypercholesterolemia?
Lomitapide
Mipomersen
Lomitamide
MOA
Inhibits MTP in enterocytes and liver.
Less formation of chylomicrons and VLDLs, less LDL
Mipomersen
MOA
Antisense oligonucleotide for poB100
Inhibits structural components of VLDLs and chylomicrons to prevent LDL synthesis
